Jmjd1c demethylates STAT3 to restrain plasma cell differentiation and rheumatoid arthritis.

Appropriate regulation of B cell differentiation into plasma cells is essential for humoral immunity while preventing antibody-mediated autoimmunity; however, the underlying mechanisms, especially those with pathological consequences, remain unclear. Here, we found that the expression of Jmjd1c, a member of JmjC domain histone demethylase, in B cells but not in other immune cells, protected mice from rheumatoid arthritis (RA). In humans with RA, JMJD1C expression levels in B cells were negatively associated with plasma cell frequency and disease severity. Mechanistically, Jmjd1c demethylated STAT3, rather than histone substrate, to restrain plasma cell differentiation. STAT3 Lys140 hypermethylation caused by Jmjd1c deletion inhibited the interaction with phosphatase Ptpn6 and resulted in abnormally sustained STAT3 phosphorylation and activity, which in turn promoted plasma cell generation. Germinal center B cells devoid of Jmjd1c also acquired strikingly increased propensity to differentiate into plasma cells. STAT3 Lys140Arg point mutation completely abrogated the effect caused by Jmjd1c loss. Mice with Jmjd1c overexpression in B cells exhibited opposite phenotypes to Jmjd1c-deficient mice. Overall, our study revealed Jmjd1c as a critical regulator of plasma cell differentiation and RA and also highlighted the importance of demethylation modification for STAT3 in B cells.

Transcranial volumetric imaging using a conformal ultrasound patch.

Accurate and continuous monitoring of cerebral blood flow is valuable for clinical neurocritical care and fundamental neurovascular research. Transcranial Doppler (TCD) ultrasonography is a widely used non-invasive method for evaluating cerebral blood flow1, but the conventional rigid design severely limits the measurement accuracy of the complex three-dimensional (3D) vascular networks and the practicality for prolonged recording2. Here we report a conformal ultrasound patch for hands-free volumetric imaging and continuous monitoring of cerebral blood flow. The 2 MHz ultrasound waves reduce the attenuation and phase aberration caused by the skull, and the copper mesh shielding layer provides conformal contact to the skin while improving the signal-to-noise ratio by 5 dB. Ultrafast ultrasound imaging based on diverging waves can accurately render the circle of Willis in 3D and minimize human errors during examinations. Focused ultrasound waves allow the recording of blood flow spectra at selected locations continuously. The high accuracy of the conformal ultrasound patch was confirmed in comparison with a conventional TCD probe on 36 participants, showing a mean difference and standard deviation of difference as -1.51 ± 4.34 cm s-1, -0.84 ± 3.06 cm s-1 and -0.50 ± 2.55 cm s-1 for peak systolic velocity, mean flow velocity, and end diastolic velocity, respectively. The measurement success rate was 70.6%, compared with 75.3% for a conventional TCD probe. Furthermore, we demonstrate continuous blood flow spectra during different interventions and identify cascades of intracranial B waves during drowsiness within 4 h of recording.

A wearable cardiac ultrasound imager.

Continuous imaging of cardiac functions is highly desirable for the assessment of long-term cardiovascular health, detection of acute cardiac dysfunction and clinical management of critically ill or surgical patients1-4. However, conventional non-invasive approaches to image the cardiac function cannot provide continuous measurements owing to device bulkiness5-11, and existing wearable cardiac devices can only capture signals on the skin12-16. Here we report a wearable ultrasonic device for continuous, real-time and direct cardiac function assessment. We introduce innovations in device design and material fabrication that improve the mechanical coupling between the device and human skin, allowing the left ventricle to be examined from different views during motion. We also develop a deep learning model that automatically extracts the left ventricular volume from the continuous image recording, yielding waveforms of key cardiac performance indices such as stroke volume, cardiac output and ejection fraction. This technology enables dynamic wearable monitoring of cardiac performance with substantially improved accuracy in various environments.

Adenosine mediates the amelioration of social novelty deficits during rhythmic light treatment of 16p11.2 deletion female mice.

Non-invasive brain stimulation therapy for autism spectrum disorder (ASD) has shown beneficial effects. Recently, we and others demonstrated that visual sensory stimulation using rhythmic 40 Hz light flicker effectively improved cognitive deficits in mouse models of Alzheimer's disease and stroke. However, whether rhythmic visual 40 Hz light flicker stimulation can ameliorate behavioral deficits in ASD remains unknown. Here, we show that 16p11.2 deletion female mice exhibit a strong social novelty deficit, which was ameliorated by treatment with a long-term 40 Hz light stimulation. The elevated power of local-field potential (LFP) in the prefrontal cortex (PFC) of 16p11.2 deletion female mice was also effectively reduced by 40 Hz light treatment. Importantly, the 40 Hz light flicker reversed the excessive excitatory neurotransmission of PFC pyramidal neurons without altering the firing rate and the number of resident PFC neurons. Mechanistically, 40 Hz light flicker evoked adenosine release in the PFC to modulate excessive excitatory neurotransmission of 16p11.2 deletion female mice. Elevated adenosine functioned through its cognate A1 receptor (A1R) to suppress excessive excitatory neurotransmission and to alleviate social novelty deficits. Indeed, either blocking the A1R using a specific antagonist DPCPX or knocking down the A1R in the PFC using a shRNA completely ablated the beneficial effects of 40 Hz light flicker. Thus, this study identified adenosine as a novel neurochemical mediator for ameliorating social novelty deficit by reducing excitatory neurotransmission during 40 Hz light flicker treatment. The 40 Hz light stimulation warrants further development as a non-invasive ASD therapeutics.

Epigenomic Profiling of Human CD4+ T Cells Supports a Linear Differentiation Model and Highlights Molecular Regulators of Memory Development.

The impact of epigenetics on the differentiation of memory T (Tmem) cells is poorly defined. We generated deep epigenomes comprising genome-wide profiles of DNA methylation, histone modifications, DNA accessibility, and coding and non-coding RNA expression in naive, central-, effector-, and terminally differentiated CD45RA+ CD4+ Tmem cells from blood and CD69+ Tmem cells from bone marrow (BM-Tmem). We observed a progressive and proliferation-associated global loss of DNA methylation in heterochromatic parts of the genome during Tmem cell differentiation. Furthermore, distinct gradually changing signatures in the epigenome and the transcriptome supported a linear model of memory development in circulating T cells, while tissue-resident BM-Tmem branched off with a unique epigenetic profile. Integrative analyses identified candidate master regulators of Tmem cell differentiation, including the transcription factor FOXP1. This study highlights the importance of epigenomic changes for Tmem cell biology and demonstrates the value of epigenetic data for the identification of lineage regulators.

Role of transient receptor potential ankyrin 1 in idiopathic pulmonary fibrosis: modulation of M2 macrophage polarization.

Idiopathic pulmonary fibrosis (IPF) poses significant challenges due to limited treatment options despite its complex pathogenesis involving cellular and molecular mechanisms. This study investigated the role of transient receptor potential ankyrin 1 (TRPA1) channels in regulating M2 macrophage polarization in IPF progression, potentially offering novel therapeutic targets. Using a bleomycin-induced pulmonary fibrosis model in C57BL/6J mice, we assessed the therapeutic potential of the TRPA1 inhibitor HC-030031. TRPA1 upregulation was observed in fibrotic lungs, correlating with worsened lung function and reduced survival. TRPA1 inhibition mitigated fibrosis severity, evidenced by decreased collagen deposition and restored lung tissue stiffness. Furthermore, TRPA1 blockade reversed aberrant M2 macrophage polarization induced by bleomycin, associated with reduced Smad2 phosphorylation in the TGF-ß1-Smad2 pathway. In vitro studies with THP-1 cells treated with bleomycin and HC-030031 corroborated these findings, highlighting TRPA1's involvement in fibrotic modulation and macrophage polarization control. Overall, targeting TRPA1 channels presents promising therapeutic potential in managing pulmonary fibrosis by reducing pro-fibrotic marker expression, inhibiting M2 macrophage polarization, and diminishing collagen deposition. This study sheds light on a novel avenue for therapeutic intervention in IPF, addressing a critical need in the management of this challenging disease.

Regulating Planarized Intramolecular Charge Transfer for Efficient Single-Phase White-Light Emission in Undoped Metal-Organic Framework Nanocrystals.

The technology of combining multiple emission centers to exploit white-light-emitting (WLE) materials by taking advantage of porous metal-organic frameworks (MOFs) is mature, but preparing undoped WLE MOFs remains a challenge. Herein, a pressure-treated strategy is reported to achieve efficient white photoluminescence (PL) in undoped [Zn(Tdc)(py)]n nanocrystals (NCs) at ambient conditions, where the Commission International del'Eclairage coordinates and color temperature reach (0.31, 0.37) and 6560 K, respectively. The initial [Zn(Tdc)(py)]n NCs exhibit weak-blue PL consisting of localized excited (LE) and planarized intramolecular charge transfer (PLICT) states. After pressure treatment, the emission contributions of LE and PLICT states are balanced by increasing the planarization of subunits, thereby producing white PL. Meanwhile, the reduction of nonradiative decay triggered by the planarized structure results in 5-fold PL enhancement. Phosphor-converted light-emitting diodes based on pressure-treated samples show favorable white-light characteristics. The finding provides a new platform for the development of undoped WLE MOFs.

SUMOylation of Smad2 mediates TGF-ß-regulated endothelial-mesenchymal transition.

Endothelial-mesenchymal transition (EndoMT) is a complex biological process in which endothelial cells are transformed into mesenchymal cells, and dysregulated EndoMT causes a variety of pathological processes. Transforming growth factor beta (TGF-ß) signaling effectively induces the EndoMT process in endothelial cells, and Smad2 is the critical protein of the TGF-ß signaling pathway. However, whether small ubiquitin-like modifier modification (SUMOylation) is involved in EndoMT remains unclear. Here, we show that Smad2 is predominantly modified by SUMO1 at two major SUMOylation sites with PIAS2α as the primary E3 ligase, whereas SENP1 (sentrin/SUMO-specific protease 1) mediates the deSUMOylation of Smad2. In addition, we identified that SUMOylation significantly enhances the transcriptional activity and protein stability of Smad2, regulating the expression of downstream target genes. SUMOylation increases the phosphorylation of Smad2 and the formation of the Smad2-Smad4 complex, thus promoting the nuclear translocation of Smad2. Ultimately, the wildtype, but not SUMOylation site mutant Smad2 facilitated the EndoMT process. More importantly, TGF-ß enhances the nuclear translocation of Smad2 by enhancing its SUMOylation and promoting the EndoMT process. These results demonstrate that SUMOylation of Smad2 plays a critical role in the TGF-ß-mediated EndoMT process, providing a new theoretical basis for the treatment and potential drug targets of EndoMT-related clinical diseases.

Evolutionary analysis of conserved non-coding elements subsequent to whole-genome duplication in opium poppy.

Whole-genome duplication (WGD) leads to the duplication of both coding and non-coding sequences within an organism's genome, providing an abundant supply of genetic material that can drive evolution, ultimately contributing to plant adaptation and speciation. Although non-coding sequences contain numerous regulatory elements, they have been understudied compared to coding sequences. In order to address this gap, we explored the evolutionary patterns of regulatory sequences, coding sequences and transcriptomes using conserved non-coding elements (CNEs) as regulatory element proxies following the recent WGD event in opium poppy (Papaver somniferum). Our results showed similar evolutionary patterns in subgenomes of regulatory and coding sequences. Specifically, the biased or unbiased retention of coding sequences reflected the same pattern as retention levels in regulatory sequences. Further, the divergence of gene expression patterns mediated by regulatory element variations occurred at a more rapid pace than that of gene coding sequences. However, gene losses were purportedly dependent on relaxed selection pressure in coding sequences. Specifically, the rapid evolution of tissue-specific benzylisoquinoline alkaloid production in P. somniferum was associated with regulatory element changes. The origin of a novel stem-specific ACR, which utilized ancestral cis-elements as templates, is likely to be linked to the evolutionary trajectory behind the transition of the PSMT1-CYP719A21 cluster from high levels of expression solely in P. rhoeas root tissue to its elevated expression in P. somniferum stem tissue. Our findings demonstrate that rapid regulatory element evolution can contribute to the emergence of new phenotypes and provide valuable insights into the high evolvability of regulatory elements.

Diatomic Iron with a Pseudo-Phthalocyanine Coordination Environment for Highly Efficient Oxygen Reduction over 150,000 Cycles.

Atomically dispersed Fe-N-C catalysts emerged as promising alternatives to commercial Pt/C for the oxygen reduction reaction. However, the majority of Fe-N-C catalysts showed unsatisfactory activity and durability due to their inferior O-O bond-breaking capability and rapid Fe demetallization. Herein, we create a pseudo-phthalocyanine environment coordinated diatomic iron (Fe2-pPc) catalyst by grafting the core domain of iron phthalocyanine (Fe-Nα-Cα-Nß) onto defective carbon. In situ characterizations and theoretical calculation confirm that Fe2-pPc follows the fast-kinetic dissociative pathway, whereby Fe2-pPc triggers bridge-mode oxygen adsorption and catalyzes direct O-O radical cleavage. Compared to traditional Fe-N-C and FePc-based catalysts exhibiting superoxo-like oxygen adsorption and an *OOH-involved pathway, Fe2-pPc delivers a superior half-wave potential of 0.92 V. Furthermore, the ultrastrong Nα-Cα bonds in the pPc environment endow the diatomic iron active center with high tolerance for reaction-induced geometric stress, leading to significantly promoted resistance to demetallization. Upon an unprecedented harsh accelerated degradation test of 150,000 cycles, Fe2-pPc experiences negligible Fe loss and an extremely small activity decay of 17 mV, being the most robust candidate among previously reported Fe-N-C catalysts. Zinc-air batteries employing Fe2-pPc exhibit a power density of 255 mW cm-2 and excellent operation stability beyond 440 h. This work brings new insights into the design of atomically precise metallic catalysts.

First-in-human study to evaluate the safety, tolerability, and population pharmacokinetic/pharmacodynamic target attainment analysis of FL058 alone and in combination with meropenem in healthy subjects.

FL058 is a novel diazabicyclooctane ß-lactamase inhibitor. This first-in-human study evaluated the safety, tolerability, and population pharmacokinetic (PK)/pharmacodynamic target attainment analysis of FL058 alone and in combination with meropenem in healthy subjects. The results showed that the maximum tolerated dose of FL058 was 3,000 mg after single-dose infusion. FL058 in combination with meropenem did not cause any grade 3 or higher adverse event when the dose was escalated up to 1,000 mg/2,000 mg. FL058 exposure PK parameters showed dose proportionality. FL058 was excreted primarily in urine. No significant PK interaction was found between FL058 and meropenem. Population PK model analysis indicated that the PK profiles of FL058 and meropenem were consistent with the two-compartment model. The impact of covariates, creatinine clearance, concomitant use of meropenem, body weight, sex, and FL058 dose, on FL058 exposure was less than 10%. FL058/meropenem combination was safe and well tolerated up to a 1,000-mg/2,000-mg dose in healthy adults. The recommended minimum dose of FL058/meropenem combination was 500 mg/1,000 mg by intravenous infusion over 2 h every 8 h based on target attainment analysis. The good safety, tolerability, and satisfactory PK profiles of FL058 alone and in combination with meropenem in this first-in-human study will support further clinical development of FL058 in combination with meropenem in patients with target infections (ClinicalTrials.gov identifiers: NCT05055687, NCT05058118, and NCT05058105).

Persistent Luminescence Lifetime-Based Near-Infrared Nanoplatform via Deep Learning for High-Fidelity Biosensing of Hypochlorite.

In light of deep tissue penetration and ultralow background, near-infrared (NIR) persistent luminescence (PersL) bioprobes have become powerful tools for bioapplications. However, the inhomogeneous signal attenuation may significantly limit its application for precise biosensing owing to tissue absorption and scattering. In this work, a PersL lifetime-based nanoplatform via deep learning was proposed for high-fidelity bioimaging and biosensing in vivo. The persistent luminescence imaging network (PLI-Net), which consisted of a 3D-deep convolutional neural network (3D-CNN) and the PersL imaging system, was logically constructed to accurately extract the lifetime feature from the profile of PersL intensity-based decay images. Significantly, the NIR PersL nanomaterials represented by Zn1+xGa2-2xSnxO4: 0.4 % Cr (ZGSO) were precisely adjusted over their lifetime, enabling the PersL lifetime-based imaging with high-contrast signals. Inspired by the adjustable and reliable PersL lifetime imaging of ZGSO NPs, a proof-of-concept PersL nanoplatform was further developed and showed exceptional analytical performance for hypochlorite detection via a luminescence resonance energy transfer process. Remarkably, on the merits of the dependable and anti-interference PersL lifetimes, this PersL lifetime-based nanoprobe provided highly sensitive and accurate imaging of both endogenous and exogenous hypochlorite. This breakthrough opened up a new way for the development of high-fidelity biosensing in complex matrix systems.

Meldonium, as a potential neuroprotective agent, promotes neuronal survival by protecting mitochondria in cerebral ischemia-reperfusion injury.

BACKGROUND: Stroke is a globally dangerous disease capable of causing irreversible neuronal damage with limited therapeutic options. Meldonium, an inhibitor of carnitine-dependent metabolism, is considered an anti-ischemic drug. However, the mechanisms through which meldonium improves ischemic injury and its potential to protect neurons remain largely unknown. METHODS: A rat model with middle cerebral artery occlusion (MCAO) was used to investigate meldonium's neuroprotective efficacy in vivo. Infarct volume, neurological deficit score, histopathology, neuronal apoptosis, motor function, morphological alteration and antioxidant capacity were explored via 2,3,5-Triphenyltetrazolium chloride staining, Longa scoring method, hematoxylin and eosin staining, terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling assay, rotarod test, transmission electron microscopy and Oxidative stress index related kit. A primary rat hippocampal neuron model subjected to oxygen-glucose deprivation reperfusion was used to study meldonium's protective ability in vitro. Neuronal viability, mitochondrial membrane potential, mitochondrial morphology, respiratory function, ATP production, and its potential mechanism were assayed by MTT cell proliferation and cytotoxicity assay kit, cell-permeant MitoTracker® probes, mitochondrial stress, real-time ATP rate and western blotting. RESULTS: Meldonium markedly reduced the infarct size, improved neurological function and motor ability, and inhibited neuronal apoptosis in vivo. Meldonium enhanced the morphology, antioxidant capacity, and ATP production of mitochondria and inhibited the opening of the mitochondrial permeability transition pore in the cerebral cortex and hippocampus during cerebral ischemia-reperfusion injury (CIRI) in rats. Additionally, meldonium improved the damaged fusion process and respiratory function of neuronal mitochondria in vitro. Further investigation revealed that meldonium activated the Akt/GSK-3ß signaling pathway to inhibit mitochondria-dependent neuronal apoptosis. CONCLUSION: Our study demonstrated that meldonium shows a neuroprotective function during CIRI by preserving the mitochondrial function, thus prevented neurons from apoptosis.

Regulation of NCOA4-mediated iron recycling ameliorates paraquat-induced lung injury by inhibiting ferroptosis.

Paraquat (PQ) is an irreplaceable insecticide in many countries for the advantage of fast-acting and broad-spectrum. However, PQ was classified as the most prevailing poisoning substance for suicide with no specific antidote. Therefore, it is imperative to develop more effective therapeutic agents for the treatment of PQ poisoning. In the present study, both the RNA-Seq and the application of various cell death inhibitors reflected that ferroptosis exerts a crucial regulatory role in PQ poisoning. Moreover, we found PQ strengthens lipid peroxidation as evidenced by different experimental approaches. Of note, pretreatment of iron chelation agent DFO could ameliorate the ferroptotic cell death and alleviate the ferroptosis-related events. Mechanistically, PQ treatment intensively impaired mitochondrial homeostasis, enhanced phosphorylation of AMPK, accelerated the autophagy flux and triggered the activation of Nuclear receptor coactivator 4-ferritin heavy chain (NCOA4-FTH) axis. Importantly, the activation of autophagy was observed prior to the degradation of ferritin, and inhibition of autophagy could inhibit the accumulation of iron caused by the ferritinophagy process. Genetic and pharmacological inhibition of ferritinophagy could alleviate the lethal oxidative events, and rescue the ferroptotic cell death. Excitingly, in the mouse models of PQ poisoning, both the administration of DFO and adeno-associated virus-mediated FTH overexpression significantly reduced PQ-induced ferroptosis and improved the pathological characteristics of pulmonary fibrosis. In summary, the current work provides an in-depth study on the mechanism of PQ intoxication, describes a framework for the further understanding of ferroptosis in PQ-associated biological processes, and demonstrates modulation of iron metabolism may act as a promising therapeutic agent for the management of PQ toxicity.

Advancements in nanomedicine: Precision delivery strategies for male pelvic malignancies - Spotlight on prostate and colorectal cancer.

BACKGROUND: Pelvic malignancies consistently pose significant global health challenges, adversely affecting the well-being of the male population. It is anticipated that clinicians will continue to confront these cancers in their practice. Nanomedicine offers promising strategies that revolutionize the treatment of male pelvic malignancies by providing precise delivery methods that aim to improve the efficacy of therapeutic outcomes while minimizing side effects. Nanoparticles are designed to encapsulate therapeutic agents and selectively target cancer cells. They can also be loaded with theragnostic agents, enabling multifunctional capabilities. OBJECTIVE: This review aims to summarize the latest nanomedicine research into clinical applications, focusing on nanotechnology-based treatment strategies for male pelvic malignancies, encompassing chemotherapy, radiotherapy, immunotherapy, and other cutting-edge therapies. The review is structured to assist physicians, particularly those with limited knowledge of biochemistry and bioengineering, in comprehending the functionalities and applications of nanomaterials. METHODS: Multiple databases, including PubMed, the National Library of Medicine, and Embase, were utilized to locate and review recently published articles on advancements in nano-drug delivery for prostate and colorectal cancers. CONCLUSION: Nanomedicine possesses considerable potential in improving therapeutic outcomes and reducing adverse effects for male pelvic malignancies. Through precision delivery methods, this emerging field presents innovative treatment modalities to address these challenging diseases. Nevertheless, the majority of current studies are in the preclinical phase, with a lack of sufficient evidence to fully understand the precise mechanisms of action, absence of comprehensive pharmacotoxicity profiles, and uncertainty surrounding long-term consequences.

Palladium(II) Modulation Enhances the Water Stability and Aqueous 99TcO4-/ReO4- Removal Performance of Metal-Organic Frameworks.

Improving the water stability of metal-organic frameworks (MOFs) is essential for their use in water pollution treatment and environmental remediation, though it remains technically challenging. Herein, we report a novel cationic MOF constructed with [Th6O4(OH)4(COO)12] units and [CoN4·Cl2] units possessing a ftw-type topology (denoted as 1-Th-Co). 1-Th-Co itself exhibited poor water stability but excellent stability following a palladium(II) modulation strategy. Experimental studies reveal that Co(II) ions in 1-Th-Co were replaced by Pd(II) ions through cation exchange in N,N-diethylformamide (yielding 1-Th-Pd). The planar PdN4 units in 1-Th-Pd were responsible for improving the water stability of the framework. As a result, 1-Th-Pd offered excellent stability, fast adsorption kinetics, and high removal ratios for 99TcO4- and ReO4- (as a 99TcO4- surrogate) in contaminated water. When used in packed columns, 1-Th-Pd can dynamically capture ReO4- from groundwater. This work provides a new avenue for improving the water stability of MOFs, offering new vistas for the decontamination of aqueous solutions containing 99TcO4- and ReO4-.

Angiography-based Fractional Flow Reserve for the Prediction of Clinical Outcomes After Drug-coated Balloon or Plain Old Balloon Angioplasty.

BACKGROUND: AccuFFRangio is a novel method for fast computation of fractional flow reserve (FFR) based on coronary angiography and computational fluid dynamics. The association between the AccuFFRangio and clinical outcomes after drug-coated balloon (DCB) or plain old balloon angioplasty (POBA) remains to be investigated. METHODS: This study included consecutive patients who underwent balloon angioplasty from December 2016 to October 2020. AccuFFRangio was calculated retrospectively based on the post-procedural angiography obtained immediately after angioplasty. The primary endpoint was major adverse cardiac events (MACE), defined as a composite of all-cause death, vessel-related myocardial infarction, and repeat target vessel revascularization. RESULTS: A total of 169 patients were retrospectively analyzed in this study. Post-procedural AccuFFRangio (hazard ratio [HR] per 0.1 increase 0.33, 95% confidence interval [CI] 0.22-0.48, p < 0.001) was an independent predictor for MACE at 2-year follow-up. Post-procedural AccuFFRangio ≤ 0.87 was determined as the optimal cutoff value to predict MACE with an area under the curve (AUC) of 0.872 (95% CI 0.813-0.919, p < 0.001). CONCLUSIONS: AccuFFRangio measured immediately after balloon angioplasty is a promising predictor of unfavorable clinical outcomes.

Aberrant brain intra- and internetwork functional connectivity in children with Prader-Willi syndrome.

PURPOSE: Prader-Willi syndrome (PWS) suffers from brain functional reorganization and developmental delays during childhood, but the underlying neurodevelopmental mechanism is unclear. This paper aims to investigate the intra- and internetwork functional connectivity (FC) changes, and their relationships with developmental delays in PWS children. METHODS: Resting-state functional magnetic resonance imaging datasets of PWS children and healthy controls (HCs) were acquired. Independent component analysis was used to acquire core resting-state networks (RSNs). The intra- and internetwork FC patterns were then investigated. RESULTS: In terms of intranetwork FC, children with PWS had lower FC in the dorsal attention network, the auditory network, the medial visual network (VN) and the sensorimotor network (SMN) than HCs (FWE-corrected, p < 0.05). In terms of internetwork FC, PWS children had decreased FC between the following pairs of regions: posterior default mode network (DMN) and anterior DMN; posterior DMN and SMN; SMN and posterior VN and salience network and medial VN (FDR-corrected, p < 0.05). Partial correlation analyses revealed that the intranetwork FC patterns were positively correlated with developmental quotients in PWS children, while the internetwork FC patterns were completely opposite (p < 0.05). Intranetwork FC patterns showed an area under the receiver operating characteristic curve of 0.947, with a sensitivity of 96.15% and a specificity of 81.25% for differentiating between PWS and HCs. CONCLUSION: Impaired intra- and internetwork FC patterns in PWS children are associated with developmental delays, which may result from neural pathway dysfunctions. Intranetwork FC reorganization patterns can discriminate PWS children from HCs. REGISTRATION NUMBER ON THE CHINESE CLINICAL TRAIL REGISTRY: ChiCTR2100046551.

Recombinant human adenovirus type 5 promotes anti-tumor immunity via inducing pyroptosis in tumor endothelial cells.

Recombinant human type 5 adenovirus (H101) is an oncolytic virus used to treat nasopharyngeal carcinoma. Owing to the deletion of the E1B-55kD and E3 regions, H101 is believed to selectively inhibit nasopharyngeal carcinoma. Whether H101 inhibits other type of tumors via different mechanisms remains unclear. In this study we investigated the effects of H101 on melanomas. We established B16F10 melanoma xenograft mouse model, and treated the mice with H101 (1 × 108 TCID50) via intratumoral injection for five consecutive days. We found that H101 treatment significantly inhibited B16F10 melanoma growth in the mice. H101 treatment significantly increased the infiltration of CD8+ T cells and reduced the proportion of M2-type macrophages. We demonstrated that H101 exhibited low cytotoxicity against B16F10 cells, but the endothelial cells were more sensitive to H101 treatment. H101 induced endothelial cell pyroptosis in a caspase-1/GSDMD-dependent manner. Furthermore, we showed that the combination of H101 with the immune checkpoint inhibitor PD-L1 antibody (10 mg/kg, i.p., every three days for three times) exerted synergic suppression on B16F10 tumor growth in the mice. This study demonstrates that, in addition to oncolysis, H101 inhibits melanoma growth by promoting anti-tumor immunity and inducing pyroptosis of vascular endothelial cells.

Application progress of deep generative models in de novo drug design.

The deep molecular generative model has recently become a research hotspot in pharmacy. This paper analyzes a large number of recent reports and reviews these models. In the central part of this paper, four compound databases and two molecular representation methods are compared. Five model architectures and applications for deep molecular generative models are emphatically introduced. Three evaluation metrics for model evaluation are listed. Finally, the limitations and challenges in this field are discussed to provide a reference and basis for developing and researching new models published in future.